What does p53 do to MDM2?
p53 and MDM2 form an auto-regulatory feedback loop. p53 stimulates the expression of MDM2; MDM2 inhibits p53 activity because it blocks its transcriptional activity, favours its nuclear export and stimulates its degradation. Different cellular signals, such as DNA-damage or oncogene activation, induce p53 activation.
What is the structure of p53?
Domain structure of p53. p53 contains a natively unfolded amino-terminal transactivation domain (TAD), which can be further subdivided into the subdomains TAD1 and TAD2, followed by a proline-rich region (PRR). The structured DNA-binding and tetramerization domains (OD) are connected through a flexible linker region.
Does MDM2 phosphorylate p53?
Although it was demonstrated that phosphorylation of Mdm2 by ATM or C-Abl kinase reduces Mdm2’s ability to inactivate p53 after DNA damage (Maya et al., 2001; Goldberg et al., 2002), the significance of Mdm2 phosphorylation in regulation of p53 activity is largely unknown.
Does MDM2 ubiquitination p53?
Mdm2 is a key repressor of p53. It is an E3 ligase that promotes p53 ubiquitination and proteasomal degradation. In addition, binding of Mdm2 to p53 can directly inhibit the transcriptional activity of p53 through a number of mechanisms. Mdm2 is ubiquitinated and is degraded by the proteasome.
What is MDM2 gene?
The murine double minute 2 (mdm2) gene encodes a negative regulator of the p53 tumor suppressor. Amplification of mdm2 or increased expression by unknown mechanisms occurs in many tumors.
How does ARF inhibit MDM2?
Our results show that ARF inhibits MDM2-mediated Rb degradation by disruption of MDM2–Rb interaction. In addition, we show that lack of ARF led to reduced Rb protein levels independent of p53, and that ARF growth suppression function is impaired in the absence of Rb.
How does p53 bind the DNA?
p53 activates or inhibits transcription by binding to specific DNA target sequences. The p53 binding site consists of two half-sites 5´-PuPuPuC(A/T)(T/A)GPyPyPy-3´, linked by a 0-13 nucleotide spacer.
What is p53 protein made of?
The p53 protein is a phosphoprotein made of 393 amino acids. It consists of four units (or domains): A domain that activates transcription factors. A domain that recognizes specific DNA sequences (core domain).
Is MDM2 phosphorylated?
MDM2 is phosphorylated by ATM, ATR, and C-Abl on sites near the C terminus (29, 40, 41). DNA damage also induces dephosphorylation of several serine residues in the acidic domain of MDM2 (3).
Why is p53 phosphorylated?
Following stress, p53 is phosphorylated at multiple residues, thereby modifying its biochemical functions required for increased activity as a transcription factor. The biochemical functions include sequence-specific DNA binding and protein-protein interactions.
How is p53 degraded?
p53 is usually kept inactive due to ubiquitination by a number of E3 ubiquitin ligases that target p53 for proteasomal degradation. The ubiquitously expressed proto-oncogene Mdm2 is the major E3 ubiquitin ligase involved in this process and is critical for regulating p53 homeostasis.
How does Mdm2 bind to the p53 transactivation domain?
MDM2 binding to the NH 2 terminal transactivation domain of p53 blocks its transcriptional activity directly ( 12, 30 ). More importantly, MDM2 functions as the E3 ligase that ubiquitinates p53 for proteasome degradation ( 14, 18 ).
What is the strength of the MDM2-p53 bond?
Experimental measurements of the strength of the p53-MDM2 bond range from a Kd of 60 to 700 n m, depending on the length of the p53 peptide ( 34 –37 ).
How does Mdm2 and p53 form a feedback loop?
Regulation of p53 by MDM2. p53 and MDM2 form an autoregulatory feedback loop. p53 stimulates the expression of MDM2; MDM2, in turn, inhibits p53 activity because it stimulates its degradation in the nucleus and the cytoplasm, blocks its transcriptional activity, and promotes its nuclear export.
What is the structure of the p53 protein?
p53 protein structure The p53 protein is active as a tetramer of 4 chains of 393 amino acids. Each chain has several domains. At the N-terminal, there are two distinct transactivation domains (TADI and TADII), a nuclear export signal (NES) followed by the proline-rich domain (PD) and the DNA binding domain (DBD) (Wang et al., 1994).